Structure and dynamics of the integrin LFA-1 I-domain in the inactive state underlie its inside-out/outside-in signaling and allosteric mechanisms.
View / Open Files
Authors
Kukic, Predrag
Alvin Leung, Hoi Tik
Bemporad, Francesco
De Simone, Alfonso
Camilloni, Carlo
Publication Date
2015-04-07Journal Title
Structure
ISSN
0969-2126
Publisher
Cell Press
Volume
23
Pages
745-753
Language
English
Type
Article
Metadata
Show full item recordCitation
Kukic, P., Alvin Leung, H. T., Bemporad, F., Aprile, F., Kumita, J., De Simone, A., Camilloni, C., & et al. (2015). Structure and dynamics of the integrin LFA-1 I-domain in the inactive state underlie its inside-out/outside-in signaling and allosteric mechanisms.. Structure, 23 745-753. https://doi.org/10.1016/j.str.2014.12.020
Abstract
Lymphocyte function-associated antigen 1 (LFA-1) is an integrin that transmits information in two directions across the plasma membrane of leukocytes, in so-called outside-in and inside-out signaling mechanisms. To investigate the structural basis of these mechanisms, we studied the conformational space of the apo I-domain using replica-averaged metadynamics simulations in combination with nuclear magnetic resonance chemical shifts. We thus obtained a free energy landscape that reveals the existence of three conformational substates of this domain. The three substates include conformations similar to existing crystallographic structures of the low-affinity I-domain, the inactive I-domain with an allosteric antagonist inhibitor bound underneath α helix 7, and an intermediate affinity state of the I-domain. The multiple substates were validated with residual dipolar coupling measurements. These results suggest that the presence of three substates in the apo I-domain enables the precise regulation of the binding process that is essential for the physiological function of LFA-1.
Sponsorship
This study was supported by the Wellcome Trust and the BBSRC.
Identifiers
External DOI: https://doi.org/10.1016/j.str.2014.12.020
This record's URL: https://www.repository.cam.ac.uk/handle/1810/247847
Rights
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
Statistics
Recommended or similar items
The following licence files are associated with this item: